Rashidi M R, Smith J A, Clarke S E, Beedham C
Pharmaceutical Chemistry, School of Pharmacy, University of Bradford, UK.
Drug Metab Dispos. 1997 Jul;25(7):805-13.
Famciclovir, a 9-substituted guanine derivative, is a new antiviral agent which undergoes rapid hydrolysis and oxidation in man to yield the active antiherpes agent, penciclovir. Studies with human liver cytosol have indicated that the oxidation of the penultimate metabolite, 6-deoxypenciclovir, to penciclovir is catalyzed by the molybdenum hydroxylase, aldehyde oxidase. In the present study the oxidation of famciclovir and 6-deoxypenciclovir with partially purified molybdenum hydroxylases from human, guinea pig, rabbit, and rat livers and bovine milk xanthine oxidase has been investigated. Famciclovir and 6-deoxypenciclovir were oxidized predominantly to 6-oxo-famciclovir and penciclovir, respectively, by human, guinea pig, and rat liver aldehyde oxidase. Small amounts of 8-oxo and 6,8-dioxo-metabolites were also formed from each substrate. Famciclovir and 6-deoxypenciclovir were good substrates for rabbit liver aldehyde oxidase but, in each case, two major metabolites were formed. 6-Deoxypenciclovir was converted to penciclovir and 8-oxo-6-deoxypenciclovir in approximately equal quantities; famciclovir was oxidized to 6-oxo-famciclovir and a second metabolite which, on the basis of chromatographic and UV spectral data, was thought to be 8-oxo-famciclovir. Two groups of Sprague Dawley rats were identified; those containing hepatic aldehyde oxidase and xanthine oxidase and those with only xanthine oxidase. These have been designated AO-active and AO-inactive rats, respectively. Famciclovir was not oxidized by enzyme from AO-inactive rats or bovine milk xanthine oxidase although 6-deoxypenciclovir was slowly converted to penciclovir by rat liver or milk xanthine oxidase. Inhibitor studies showed in human, guinea pig, and rabbit liver that xanthine oxidase did not contribute to the oxidation of famciclovir and 6-deoxypenciclovir; thus it is proposed that drug activation in vivo would be catalyzed solely by aldehyde oxidase.
泛昔洛韦是一种9-取代鸟嘌呤衍生物，是一种新型抗病毒药物，在人体内会迅速水解和氧化，生成活性抗疱疹药物喷昔洛韦。对人肝细胞溶胶的研究表明，倒数第二个代谢产物6-脱氧喷昔洛韦氧化为喷昔洛韦是由钼羟化酶醛氧化酶催化的。在本研究中，研究了用来自人、豚鼠、兔和大鼠肝脏的部分纯化钼羟化酶以及牛乳黄嘌呤氧化酶对泛昔洛韦和6-脱氧喷昔洛韦的氧化作用。泛昔洛韦和6-脱氧喷昔洛韦分别被人、豚鼠和大鼠肝脏醛氧化酶主要氧化为6-氧代泛昔洛韦和喷昔洛韦。每种底物还生成少量的8-氧代和6,8-二氧代代谢产物。泛昔洛韦和6-脱氧喷昔洛韦是兔肝脏醛氧化酶的良好底物，但在每种情况下，都会形成两种主要代谢产物。6-脱氧喷昔洛韦以大致相等的量转化为喷昔洛韦和8-氧代-6-脱氧喷昔洛韦；泛昔洛韦被氧化为6-氧代泛昔洛韦和第二种代谢产物，根据色谱和紫外光谱数据，该代谢产物被认为是8-氧代泛昔洛韦。鉴定出两组斯普拉格-道利大鼠；一组含有肝醛氧化酶和黄嘌呤氧化酶，另一组仅含有黄嘌呤氧化酶。它们分别被指定为AO活性大鼠和AO非活性大鼠。泛昔洛韦不会被AO非活性大鼠的酶或牛乳黄嘌呤氧化酶氧化，尽管6-脱氧喷昔洛韦会被大鼠肝脏或乳黄嘌呤氧化酶缓慢转化为喷昔洛韦。抑制剂研究表明，在人、豚鼠和兔肝脏中，黄嘌呤氧化酶对泛昔洛韦和6-脱氧喷昔洛韦的氧化没有作用；因此，有人提出体内药物激活仅由醛氧化酶催化。
